Ca2+ influx through Ca2+ release–activated Ca2+ (CRAC) channels at the plasma membrane (PM) in response to the depletion of Ca2+ stored in the endoplasmic reticulum (ER) is an essential component of Ca2+ signaling mechanisms in nonexcitable cells. CRAC channels composed of pore-forming Orai subunits are gated by STIM1 proteins, which are ER-localized Ca2+ sensors that oligomerize and cluster near Orai channels at ER-PM junctions after depletion of ER-stored Ca2+; however, the mechanism by which STIM1 activates Orai channels is unclear. Two studies now provide evidence that Orai1 function is mediated by a direct interaction with a discrete region within STIM1. Yuan et al. found that a STIM1 fragment consisting of residues 344 to 442, which they named the STIM1 Orai activating region (SOAR), recapitulated the effects of STIM1 on Ca2+ influx in transfected HEK cells. SOAR coimmunoprecipitated with Orai1 but not with a mutant Orai1 lacking its C terminus. Although SOAR mediated the activity of the Orai channel, another region of STIM1 mediated clustering of STIM1 and Orai1 in response to depletion of ER-stored Ca2+; this clustering was insufficient to mediate Ca2+ influx. Deletion of the N terminus of Orai1 prevented its activation by full-length STIM1 but not by SOAR. Park et al. found that a STIM1 peptide consisting of residues 342 to 448, termed the CRAC activation domain (CAD), activated Orai1 channels and bound directly to Orai1. Consistent with the other study, coclustering of STIM1 and Orai1, mediated by a polybasic region within STIM1, was insufficient to trigger Ca2+ influx. Together, these studies suggest a mechanism whereby clustering of STIM1 and Orai channels enables the binding of SOAR/CAD to Orai to activate the channel.